The antitumor plant alkaloid camptothecin (CPT) is a broad-spectrum anticancer agent that targets DNA topoisomerase I. Although CPT has shown promising antitumor activity in vitro and in vivo, it has not been clinically used because of its low therapeutic efficacy and severe toxicity. Among CPT analogues, irinotecan hydrochloride (CPT-11) has recently been shown to be active against colorectal, lung, and ovarian cancer. CPT-11 itself is a prodrug and is converted to 7-ethyl-10-hydroxy-CPT (known as SN-38), a biologically active metabolite of CPT-11, by carboxylesterases in vivo, having the following chemical structure:

SN-38 exhibits up to 1,000-fold more potent cytotoxic activity against various cancer cells in vitro than CPT-11. Although CPT-11 is converted to SN-38 in the liver and tumor, the metabolic conversion rate is <10% of the original volume of CPT-11. In addition, the conversion of CPT-11 to SN-38 varies among patients due to inherent variations carboxylesterase activity. Thus, SN-38 has an advantage over its camptothecin precursors in that it does not require activation in vivo by the liver.
Notwithstanding the fact that SN-38 is more effective than CPT-11 as an antineoplastic agent, SN-38 is exceedingly insoluble in aqueous solutions. Therefore, no formulation for administration of SN-38 to a patient has yet been developed. Thus, formulations are needed that improve SN-38 efficacy such that SN-38 can be used effectively in the treatment of diseases associated with cellular proliferation. Such a formulation should have suitable solubility and toxicity characteristics and will be useful in the treatment of certain proliferative diseases such as cancer.
Rationally-designed, nanoscopic drug carriers, or “nanovectors,” offer a promising approach to achieving these goals due to their inherent ability to overcome many biological barriers. Moreover, their multi-functionality permits the incorporation of cell-targeting groups, diagnostic agents, and a multitude of drugs in a single delivery system. Polymer micelles, formed by the molecular assembly of functional, amphiphilic block copolymers, represent one notable type of multifunctional nanovector.
Polymer micelles are particularly attractive due to their ability to deliver hydrophobic therapeutic agents. In addition, the nanoscopic size of polymeric micelles allows for passive accumulation in diseased tissues, such as solid tumors, by the enhanced permeation and retention (EPR) effect. Using appropriate surface functionality, polymer micelles are further decorated with cell-targeting groups and permeation enhancers that can actively target diseased cells and aid in cellular entry, resulting in improved cell-specific delivery.
Drug delivery vehicles are needed, which are stable to post-administration dilution, can avoid biological barriers (e.g. reticuloendothelial system (RES) uptake), and deliver drugs in response to the physiological environment encountered in diseased tissues, such as solid tumors.
The invention provides such a drug delivery method to deliver SN-38 for the treating, stabilizing, or lessening the severity or progression of proliferative diseases, such as cancer, with SN-38 encapsulated in a multiblock copolymer stabilized with iron.
These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.